Preprint Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome, 2025, DecodeMe Collaboration

[duncan]

Does a pathogen, probably a virus, ever actually infect a neuron directly?

My understanding is viruses and bacteria can infect neurons directly. Herpes and borrelia, respectively, would be examples.

 

[jnmaciuch]

Does a pathogen, probably a virus, ever actually infect a neuron directly? We have non immunological genes affecting neurons, immunological genes that don't necessarily affect neurons, probably explicitly immune related genes that specifically affect neurons too - but i suppose that doesn't have to mean a neuron is dealing with a pathogen directly. I know S4ME is not very keen on the viral reservoir idea aka a brain infection but why is that?

Yes there are neurotropic viruses definitely. I think there a couple points of evidence against persistent infection, but they're not conclusive.

1) If there was a persistent viral infection, you'd expect that nearly all of the trials using immunosuppressants would lead to dramatic worsening of disease as the virus is able to replicate utterly unchecked. There might be some obscure reason why this doesn't happen, I suppose. But highly unlikely.

2) The type of virus that causes a long term illness like ME/CFS but doesn't result in progressive deterioration and mortality would probably have to be a latent virus. Even hepatitis, which has a very slow course, has a progressive pattern.
It is unlikely that we're all suffering from the same virus, meaning that it would have to be a non-pathogen-specific effect of latent viral infection. If it is a set of different latent viruses, the question then becomes how does a virus in the latent state induce persistent issues in some but not others. Nearly half of adults have latent herpres virus in their nervous system and are fine. So if viral persistence is relevant in ME/CFS, it has to be viral reservoir + something else important.

 

[ElephantNerd]

Hi. I've posted this elsewhere on Science for ME, but think it's important to leave here too.
About the "only a 1% difference between [the frequencies of] those with ME and controls". This small "effect size" does not matter if you're focused on drug discovery. This is because the success rate from clinical development to approval "is largely unaffected by genetic effect size", see https://www.nature.com/articles/s41586-024-07316-0. The reason for this is subtle but important. Even when DNA variation tweaks biology only slightly, this variation highlights what biological aspects need changing via drugs. And these drugs can be made to alter biology to a far, far greater extent than the genes can.

(This as the answer to the question about how can small genetic differences between cases controls produce valuable information )

Is it also true that somebody who doesn't have a relevant genetic difference in a particular gene can benefit from any such drug targeting the biology behind the gene?

In other words, can information from genetic study help all those people with the illness who don't have relevant genetic differences?

I've been trying to understand this through a made-up analogy. Thought I might share it to see if it holds and if others find it useful or not.

Suppose an illness is caused by a structure somewhere in the body that lets cells through that it should hold back, like a dam that is breaking. There is one gene X that helps to create a simple protein that acts as one of many support structures in the dam.

One variant of the gene creates a slightly stronger protein than the other variant to support the dam. The difference between the two proteins is minor and this protein is only a minuscule part of what holds the dam. There are many other mechanisms involved in the strength of the dam that involves feedback loops and complex interactions. These are much more important but gene X is simple and straightforward. It only has one job.

In GWAS of the illness, gene X might show up with a very small effect size. The others don't show up because the mechanisms are too complex and intertwined or there is a signal but it's ambiguous and hard to interpret. Luckily gene X points to the problem: the dam is breaking! And luckily scientists know a lot of biology so that they can do much more to support the dam than gene X could by coding its protein. They can create drugs that ensure the dam no longer breaks.

So in this analogy, the dam might be breaking even in those with the stronger protein from gene X. And fixing the dam might cause physiological changes and benefits that are out of proportion to the effect size of gene X.

Now I only hope that real life works like this as well!

Not to echo or parrot, but does this mean that the tissues affected by the genes found in MECFS are good targets for future research (both diagnostic and treatments)? Specifically they have found areas of the brain to look at, as well as areas in the immune system, and the mitochondria..... These are promising targets for future research and are likely to be involved in the disease process.... yes?

I'm a bit brain fogged pls so let me know if this is accurate summary or how I can improve the wording.

Thanks to all you science experts explaining this to me

 

[duncan]

1) If there was a persistent viral infection, you'd expect that nearly all of the trials using immunosuppressants would lead to dramatic worsening of disease as the virus is able to replicate utterly unchecked. There might be some obscure reason why this doesn't happen, I suppose. But highly unlikely.

Not necessarily, especially if we are looking at highly specific viral reservoirs.

) The type of virus that causes a long term illness like ME/CFS but doesn't result in progressive deterioration and mortality would probably have to be a latent virus. Even hepatitis, which has a very slow course, has a progressive pattern.
It is unlikely that we're all suffering from the same virus, meaning that it would have to be a non-pathogen-specific effect of latent viral infection. If it is a set of different latent viruses, the question then becomes how does a virus in the latent state induce persistent issues in some but not others. Nearly half of adults have latent herpres virus in their nervous system and are fine. So if viral persistence is relevant in ME/CFS, it has to be viral reservoir + something else important.

It could be a combination of agents, and why some get sick and others do not goes back to the right combination.

These are great points @jnmaciuch. I also agree we are looking at several different pathogens among our community as at least triggering events, but the idea of sanctuary reservoirs may hold some merit.

ETA: I see you've considered reservoirs.